The present invention relates to novel benzimidazole thiophene compounds, pharmaceutical formulations comprising these compounds, and the use of these compounds in therapy.
Polo-like kinases (“PLK”) are evolutionarily conserved serine/threonine kinases that play critical roles in regulating processes in the cell cycle. PLK plays a role in the entry into and the exit from mitosis in diverse organisms from yeast to mammalian cells. PLK includes PLK1, PLK2, PLK3 and PLK4.
Overexpression of PLK1 appears to be strongly associated with neoplastic cells (including cancers). A published study has shown high levels of PLK1 RNA expression in >80% of lung and breast tumors, with little to no expression in adjacent normal tissue. Several studies have shown correlations between PLK expression, histological grade, and prognosis in several types of cancer. Significant correlations were found between percentages of PLK-positive cells and histological grade of ovarian and endometrial cancer (P<0.001). These studies noted that PLK is strongly expressed in invading endometrial carcinoma cells and that this could reflect the degree of malignancy and proliferation in endometrial carcinoma. Using RT-PCR analysis, PLK overexpression was detected in 97% of esophageal carcinomas and 73% of gastric carcinomas as compared to the corresponding normal tissues. Further, patients with high levels of PLK overexpression in esophageal carcinoma represented a significantly poorer prognosis group than those with low levels of PLK overexpression. In head and neck cancers, elevated mRNA expression of PLK1 was observed in most tumors; a Kaplan-Meier analysis showed that those patients with moderate levels of PLK1 expression survived longer than those with high levels of PLK1 expression. Analysis of patients with non-small cell lung carcinoma showed similar outcomes related to PLK1 expression.
PCT Publication No. WO2004/014899 to SmithKline Beecham discloses novel benzimidazole thiophene compounds of formula (I):
wherein:    R1 is selected from the group consisting of H, alkyl, alkenyl, alkynyl, —C(O)R7, —CO2R7, —C(O)NR7R8, —C(O)N(R7)OR8, —C(O)N(R7)—R2—OR8, —C(O)N(R7)-Ph, —C(O)N(R7)—R2-Ph, —C(O)N(R7)C(O)R8, —C(O)N(R7)CO2R8, —C(O)N(R7)C(O)NR7R8, —C(O)N(R7)S(O)2R8, —R2—OR7, —R2—O—C(O)R7, —C(S)R7, —C(S)NR7R8, —C(S)N(R7)-Ph, —C(S)N(R7)—R2-Ph, —R2—SR7, —C(═NR7)NR7R8, —C(NR7)N(R8)-Ph, —C(═NR7)N(R8)—R2-Ph, —R2—NR7R8, —CN, —OR7, —S(O)fR7, —S(O)2NR7R8, —S(O)2N(R7)-Ph, —S(O)2N(R7)—R2-Ph, —NR7R8, N(R7)-Ph, —N(R7)—R2-Ph, —N(R7)—SO2R8 and Het;    Ph is phenyl optionally substituted from 1 to 3 times with a substituent selected from the group consisting of halo, alkyl, —OH, —R2—OH, —O-alkyl, —R2—O-alkyl, —NH2, —N(H)alkyl, —N(alkyl)2, —CN and —N3;    Het is a 5-7 membered heterocycle having 1, 2, 3 or 4 heteroatoms selected from N, O and S, or a 5-6 membered heteroaryl having 1, 2, 3 or 4 heteroatoms selected from N, O and S, each optionally substituted from 1 to 2 times with a substituent selected from the group consisting of halo, alkyl, oxo, —OH, —R2—OH, —O-alkyl, —R2—O-alkyl, —NH2, —N(H)alkyl, —N(alkyl)2, —CN and —N3;    Q1 is a group of formula: —(R2)a—(Y1)b—(R2)c—R3     a, b and c are the same or different and are each independently 0 or 1 and at least one of a or b is 1;    n is 0, 1, 2, 3 or 4;    Q2 is a group of formula: —(R2)aa—(Y2)bb—(R2)cc—R4 or two adjacent Q2 groups are selected from the group consisting of alkyl, alkenyl, —OR7, —S(O)fR7 and —NR7R8 and together with the carbon atoms to which they are bound, they form a C5-6cycloalkyl, C5-6cycloalkenyl, phenyl, 5-7 membered heterocycle having 1 or 2 heteroatoms selected from N, O and S, or 5-6 membered heteroaryl having 1 or 2 heteroatoms selected from N, O and S;    aa, bb and cc are the same or different and are each independently 0 or 1;    each Y1 and Y2 is the same or different and is independently selected from the group consisting of —O—, —S(O)f—, —N(R7)—, —C(O)—, —OC(O)—, —CO2—, —C(O)N(R7)—, —C(O)N(R7)S(O)2—, —OC(O)N(R7)—, —OS(O)2—, —S(O)2N(R7)—, —S(O)2N(R7)C(O)—, —N(R7)S(O)2—, —N(R7)C(O)—, —N(R7)CO2— and —N(R7)C(O)N(R7)—;    each R2 is the same or different and is independently selected from the group consisting of alkylene, alkenylene and alkynylene;    each R3 and R4 is the same or different and is each independently selected from the group consisting of H, halo, alkyl, alkenyl, alkynyl, —C(O)R7, —C(O)NR7R8, —CO2R7, —C(S)R7, —C(S)NR7R8, —C(═NR7)R8, —C(═NR7)NR7R8, —CR7═N—OR7, —OR7, —S(O)fR7, —S(O)2NR7R8, —NR7R3, —N(R7)C(O)R8, —N(R7)S(O)2R8, —NO2, —CN, —N3 and a group of formula (ii):
                wherein:        Ring A is selected from the group consisting of C5-10cycloalkyl, C5-10cycyloalkenyl, aryl, 5-10 membered heterocycle having 1, 2 or 3 heteroatoms selected from N, O and S and 5-10 membered heteroaryl having 1, 2 or 3 heteroatoms selected from N, O and S        each d is 0 or 1;        e is 0, 1, 2, 3 or 4;        each R6 is the same or different and is independently selected from the group consisting of H, halo, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, Ph, Het, —CH(OH)—R2—OH, —C(O)R7, —CO2R7, —CO2—R2-Ph, —CO2—R2—Het, —C(O)NR7R8, —C(O)N(R7)C(O)R7, —C(O)N(R7)CO2R7, —C(O)N(R7)C(O)NR7R8, —C(O)N(R7)S(O)2R7, —C(S)R7, —C(S)NR7R8, —C(═NR7)R8, —C(═NR7)NR7R8, —CR7═N—OR8, ═O, —OR7, —OC(O)R7, —OC(O)Ph, —OC(O)Het, —OC(O)NR7R8, —O—R2—S(O)2R7, —S(O)fR7, —S(O)2NR7R8, —S(O)2Ph, —S(O)2Het, —NR7R8, —N(R7)C(O)R8, —N(R7)CO2R8, —N(R7)—R2—CO2R8, —N(R7)C(O)NR7R8, —N(R7)—R2—C(O)NR7R8, —N(R7)C(O)Ph, —N(R7)C(O)Het, —N(R7)Ph, —N(R7)Het, —N(R7)C(O)NR7—R2—NR7R8, —N(R7)C(O)N(R7)Ph, —N(R7)C(O)N(R7)Het, —N(R7)C(O)N(R7)—R2—Het, —N(R7)S(O)2R8, —N(R7)—R2—S(O)2R8, —NO2, —CN and —N3;            wherein when Q1 is defined where b is 1 and c is 0, R3 is not halo, —C(O)R7, —C(O)NR7R8, —CO2R7, —C(S)R7, —C(S)NR7R8, —C(═NR7)R8, —C(═NR7)NR7R8, —CR7═N—OR7—OR7, —S(O)fR7, —S(O)2NR7R8, —NR7R8, —N(R7)C(O)R8, —N(R7)S(O)2R8, —NO2, —CN or —N3;    wherein when Q2 is defined where bb is 1 and cc is 0, R4 is not halo, —C(O)R7, —C(O)NR7R8, —CO2R7, —C(S)R7, —C(S)NR7R8, —C(═NR7)R8, —C(═NR7)NR7R8, —CR7═N—OR7, —OR, —S(O)fR7, —S(O)2NR7R8, —NR7R8, —N(R7)C(O)R8, —N(R7)S(O)2R8, —NO2, —CN or —N3;    R5 is selected from the group consisting of H, halo, alkyl, cycloalkyl, OR7, —S(O)fR7, —NR7R8, —NHC(O)R7, —NHC(O)NR7R8 and —NHS(O)2R7;    f is 0, 1 or 2; and    each R7 and each R8 are the same or different and are each independently selected from the group consisting of H, alkyl, alkenyl, alkynyl, cycloalkyl and cycloalkenyl;    wherein when R1 is —CO2CH3 and n is 0, Q1 is not —OH;or a pharmaceutically acceptable salt, solvate or physiologically functional derivative thereof.
Also disclosed are pharmaceutical compositions containing these compounds, processes for their preparation and methods for treatment of conditions mediated by PLK using these compounds.